Aripiprazole is an atypical antipsychotic agent useful for the treatment of schizophrenia. Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. Onset of schizophrenia typically occurs between the age of 16 and 25 and affects 1 in 100 individuals worldwide. It is more prevalent than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome. Moreover, early therapeutic intervention may avert costly hospitalization.
U.S. Pat. No. 4,734,416 and U.S. Pat. No. 5,006,528, both assigned to Otsuka, describe aripiprazole and processes for its preparation. These patents also disclose various salts of aripiprazole and their preparation. Preparation of conventional anhydrous aripiprazole Type 1 also was disclosed in Fourth Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996). According to the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology, aripiprazole anhydride crystals are manufactured by heating, at 80° C., aripiprazole hydrate previously re-crystallized from an aqueous ethanol solution.
WO 03/026659 (corresponding to U.S. Publication 2004/0058935) also teaches a method of preparing a conventional hydrate of aripiprazole hydrate in which crude aripiprazole crystals are dissolved in a hydrous organic solvent, the solution is heated and then cooled. As described, the organic solvent is one which is miscible with water, such as for example an alcohol, acetone, an ether and their mixtures. Ethanol is apparently preferred. The amount of water in the hydrous solvent can be 10-25% by volume of the solvent, or preferably close to 20% by volume.
US Patent Publication 2005/0277650 alleges that the aripiprazole hydrate prepared as per WO 03/026659 does not provide consistent results and that by an altered process conventional aripiprazole hydrate can be prepared with more consistent results.
In particular, US Patent Publication 2005/0277650 describes a process for preparing aripiprazole hydrate in which aripiprazole is dissolved in an aqueous, organic solvent; the solution is heated to a temperature of above about 67° C.; the heated solution is seeded with aripiprazole hydrate crystals at a temperature of above about 67° C.; the so-seeded solution is cooled to a temperature in the range of about 50° C. to about 55° C. and is maintained at that temperature as crystals form; followed by further cooling of the solution to a temperature in the range of about 0° C. to about 10° C. and maintaining such temperature as crystals form; separating the crystals from the cooled solution; and drying the separated crystals at a temperature of about 45° C. to about 50° C. until the water content of the dried crystals is about 3 to about 4.5 percent by weight.